Prostate cancer (PCA) is a common and clinically heterogeneous disease with marked variability in progression. This proposal focuses on characterizing a novel translocation in PCA identified by our group, and examining the role of the translocation in disease progression. By applying a new bioinformatics approach, our group identified a common translocation in PCA, involving the tightly androgen regulated gene TMPRSS2 (21q22.3) and ETS transcription factor family members, either ERG (21q22.2) or ETV1 (7p21.2). This translocation is detected in invasive PCA and in 20% of high-grade prostatic intraepithelial neoplasia (PIN). TMPSS2-ERG PCA are associated with higher tumor stage and PCA specific death. TMPRSS2 is one of the most highly androgen regulated genes. Since our original report, we have further discovered that approximately 60% of tumors with TMPRSS2-ETS translocations harbor deletions on chromosome 21 involving the region between TMPRSS2 and ERG. The presence of translocation-associated deletions, as seen in CML, may provide important insight into the clinical and genetic heterogeneity of PCA. Therefore, our overarching hypothesis is that the TMPRSS2-ETS family oncogene fusion proteins drive PCA molecular diversity and clinical progression. We propose testing this hypothesis by pursuing the following specific aims: In Aim 1, we will characterize the frequency and extent of deletions associated with the TMPRSS2-ETS translocations in PCA. In Aim 2, we will identify critical genomic alterations associated with the distinct TMPRSS2-ETS family translocations and deletions. In Aim 3, we will develop in situ tests to evaluate fusion status as a predictor of PCA specific death or development of metastatic disease. At the conclusion of this proposal, we will have characterized the frequency of TMPRSS2-ETS translocations and deletions in a wide range of PCA samples (n>150) and a population-based cohort (n=1275). We will develop optimized FISH assays to sub-classify PCAs and identify secondary molecular alterations associated with the translocation/deletion status. Finally, we will determine if FISH assays (or other in situ tests) can be employed as a prognostic biomarker.